The present invention relates to an improved pharmaceutical formulation for indomethacin and more particularly relates to a solid dosage, constant order release indomethacin formulation.
The number of people who have arthritis is increasing. It is currently estimated that between 35-40 million people in the United States alone, or one in every seven individuals, have arthritic symptoms which require medical treatment. There will be one person every thirty-three seconds who will develop symptomatic arthritis and need medical treatment.
Even with the introduction of newer, non-steroidal drugs, such as indomethacin, naproxen, fenoprofen, ibuprofen and the like, aspirin remains the primary drug of choice for the treatment of the arthritic patient. However, there are some inflammatory joint diseases that are not easily managed with aspirin alone or where aspirin may not be indicated. These special situations are acute gouty arthritis, rheumetoid spondylitis and severe degenerative osteoarthritis of the hip.
When aspirin alone is ineffective, or cannot be tolerated, the non-steroidal anti-inflammatory drugs are used. The non-steroidal anti-inflammatory agents fall into three distinct chemical categories as noted in the reference pharmacology textbook, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 6th Edition, Section V, Chapter 28, pages 705-713: (1) indole acetic acid derivatives which include indomethacin, a methylated indole derivative and sulindac, a fluromethinyl-sulfinyl indole derivative; (2) fenamates, a family of aspirin-like drugs that are derivatives of N-phenylanthranilic acid, including mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamic acids; and (3) propionic acid derivatives. The latter group comprises the most common and widely used forms of non-steroidal phenylalkanoic acids and presently includes ibuprofen, naproxen, fenoprofen, flurbiprofen and ketoprofen.
While these compounds share common pharmacological behavior, they are distinct chemical entities, and because of their differences in chemical structure, pharmaceutical formulations that are appropriate for one or several of the above compounds, are not necessarily operable for all groups or for all members of a given group.
Indomethacin was the first commercially available, non-steroidal anti-inflammatory agent in the United States, and the product met with enormous commercial success. However, while the drug is more potent than aspirin as an anti-inflammatory agent, and has been found to possess analgesic properties as well, the severe side effects, particularly the severe gastrointestinal side effects which, on occassion have resulted in patient deaths, created a need for alternative therapy and resulted in the development and introduction of other non-steroidal anti-inflammatory agents.
However, despite its side effects, indomethacin is a very valuable therapeutic agent for conditions which do not respond to salicylate treatment, and considerable work has been done to provide improved formulations of the drug with lessened side effects. See for example U.S. Pat. Nos. 4,173,626; 4,228,160 and 4,228,161.
Much of the prior work concentrated on sustained release indomethacin preparations as methacrylic acid ester beads. See Dittgen et al Pharmazie 32(3)p.185(1977) in Chemical Abstracts 87:11555g(1977), Garcia Diss. Abstr. Int. B 38(2)pp.602-3(1977) in Chemical Abstracts 87:161724a(1977), Dittgen et al Gyogyszergszet 20(7)pp.260-262(1976) in Chemical Abstracts 87:189376h(1977); Kala et al, Pharmazie 31(11)pp. 783-9(1976) in Chemical Abstracts 86:60497c(1977) and Dittgen et al Gyogyszergszet 20(71)pp.260-2(1976) in Chemical Abstracts 85:198123p(1976).
U.S. Pat. No. 4,173,626 discloses a sustained release indomethacin capsule containing uncoated indomcthacin pellets, indomethacin pellets coated with a slow dissolving material and non-medicated pellets.
U.S. Pat. No. 4,228,161 discloses an anti-inflammatory combination having reduced ulcerogenicity comprising indomethacin and a phenylbenzoic acid compound.
U.S. Pat. No. 4,228,160 provides a complex of cyclodextrin and indomethacin which is taught to have substantially reduced ulcergenicity.
It is clear that the prior art has been concerned with reducing the ulcergenicity of indomethacin, and that while a vast body of prior art exists in the field of sustained release, buffered, enteric coated and like formulations, there has not been a simple solution to the problem posed by indomethacin.
The present invention provides an improved indomethacin formulation. Specifically, a constant release rate, solid dosage form indomethacin tablet having lessened gastrointestinal side effects, and which is simpler and less costly to produce.